Clinical Laboratory Strategies: January 23, 2008

Predicting Long-term Mortality After ACS: A Role for H-FABP?
By Phil Kibak

Although heart type fatty acid binding protein (H-FABP) was first noted as a marker of myocardial infarction (MI) in 1988, initial studies using nonspecific polyclonal antibody assays were disappointing. This issue of Strategies examines results of a recent study that suggests that H-FABP predicts long-term mortality after acute coronary syndrome (ACS) and identifies high-risk patients in a manner that is additive to the Global Registry of Acute Coronary Events (GRACE) clinical risk factors, troponin, and CRP.

Over the past decade, cardiac troponins T and I have come to be acknowledged as the “gold standard” biomarkers for diagnosing heart damage and assessing future risk in patients who have experienced acute coronary syndrome (ACS). However, troponins have several important limitations, including their limited sensitivity in detecting recurrent myocardial injury. Now researchers are investigating heart-type fatty acid binding protein (H-FABP), a low-molecular-weight protein involved in the intracellular uptake and buffering of free fatty acids in the myocardium, to see if it improves identification of high-risk patients. New research published in the Journal of the American College of Cardiology (JACC 2007; 50: 21 2061-2067) by a team of scientists at the University of Leeds (Leeds, U.K.) showed that H-FABP was powerfully and independently associated with the risk of death when measured within 12–24 hours of symptom onset and identified patients at increased risk of death even when troponin levels were normal. The research suggests that H-FABP has a role in predicting all-cause mortality after ACS.

Troponin Not a Perfect Biomarker

“Our findings suggest that raised concentrations of H-FABP are strongly predictive of mortality in patients who have experienced a cardiac event, and can identify patients who are at high risk across the full range of troponin concentrations,” said Dr. Julian Barth, Consultant Chemical Pathologist at Leeds General Infirmary and one of the authors of the study. “The occurrence of a negative test result for both troponin I and H-FABP was associated with zero mortality before six months.”

In the prospective, observational study, the team measured H-FABP 12–24 hours after the onset of symptoms in 1,448 patients with ACS. After 12 months of follow-up, 296 patients died. For analysis, patients were divided into quartiles based on H-FABP levels— quartile 1 (<6.38 μg/L), quartile 2 (6.38–12.39 μg/L), quartile 3 (12.39–36.2 μg/L), and quartile 4 (>36.2 μg/L). Multivariate analysis showed that H-FABP quartiles strongly predicted outcome. The adjusted hazard ratios (HRs) for H-FABP quartiles were 1.0 for quartile 1; HR 2.32 (95% CI, 1.25–4.30) for quartile 2; HR 3.17 (95% CI, 1.73–5.82) for quartile 3; and 4.88 ( 95% CI; 2.67–8.93) for quartile 4. The crude all-cause, 1-year mortality for unstable angina patients with H-FABP <5.8 μg/L (99th percentile) was 2.1%, compared with 22.9% for patients above this cutoff. The adjusted all-cause mortality HR in this group was 11.35 (95% CI, 2.00–64.34). Moreover, for individuals who were considered troponin negative, defined as ≤0.06 μg/L, the researchers found that the H-FABP results identified high-risk patients.

“Troponin is cited as the diagnostic test of choice for defining acute myocardial infarction by all of the major consensus statements, but it does not identify everyone with a myocardial infarct, nor does it offer very good prediction regarding outcome,” Barth said. “Our study used the best possible troponin I assay available at the time and H-FABP identified patients with confirmed myocardial infarction who had undetectable troponin and who subsequently died. These patients would have been identified by H-FABP and would have been offered possible life-saving treatments.”

Room for Other Markers in Prediction Algorithms

James A. de Lemos, MD, Associate Professor of Medicine at the University of Texas Southwestern Medical Center (Dallas, Texas), who co-authored an accompanying editorial with Michelle O’Donoghue, MD, Research Fellow at Massachusetts General Hospital (Boston, Mass.), said that H-FABP provides independent prognostic information over cardiac troponins, and that use of this as a biomarker merits further study. “These findings raise research awareness, but there’s a long way to go before this is ready for clinical application,” de Lemos maintained. “What this does is tell us how complex the release kinetics of troponins are and that these markers appear to be non-redundant, at least for risk stratification.”

“One thing we don’t know at present is a way to define the population of patients who have high H-FABP levels and low troponin levels after an ACS event,” he said. “The cause of death in these cases isn’t clearly discernible—it’s uncertain that what we’re seeing is a myocardial necrosis signal, because in such an instance you would expect the troponin level to be elevated.”

According to de Lemos and Donoghue, there were several limitations to the study. Few subjects with unstable angina were included and the investigators did not measure myoglobin, elevated levels of which also have been associated with an increased risk of death and heart failure after ACS. Additional direct comparisons are needed to fully establish the superiority of H-FABP over myoglobin for risk stratification, they wrote.

“Someday, H-FABP may be a truly clinically useful marker,” said de Lemos. “But first we need to figure out why this biomarker provides information for death and heart failure that is independent of and superior to troponin. The answer will teach us as much or more about troponin as it does about H-FABP.” 

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